Abstract Chronic heart failure, the final step of different cardiovascular diseases (CVD), remains the leading cause of cardiovascular death without a cure. To date, the therapeutic approaches by blocking or inhibiting over-activated single pathway such as inflammatory cytokines and oxidative stress which have been firmly established to play a causative role in CVD turn out to be ineffective or even harmful. In this context, the therapeutic concept of traditional herb medicine that aims to maintain systemic homeostasis by orchestrating multiple signaling pathways rather than blocking or inhibiting single over-activated signaling pathway raises a novel research direction. However, this concept has always been criticized as the 'mystical' claim for herb medicines to treat CVD, due to the contradictory findings and the lack of mechanistic analysis of herb medicine's efficacy and safety for the treatment of CVD. Indeed, the molecular mechanism by which herb medicines protect against maladaptive cardiac remodeling and heart failure remains to be established. Utilizing a standardized American ginseng extract from the National Research Council of Canada, Institute for National Measurement Standards (NRCC-INMS) under the guidelines of National Center for Complementary and Alternative Medicine (NCCAM), we have mechanistically explored the cardiac protective actions of ginseng, the root of genus Panax that has been used as a folk medicine for several thousand years in Asian countries. Our findings strongly support a novel working hypothesis that American ginseng suppresses oxidative stress and inflammatory responses, as well as the subsequent maladaptive cardiac remodeling and dysfunction via coordinating autophagic activity and Nrf2 signaling in the heart. To test this hypothesis, we propose three specific aims as follows: Aim 1. To determine role of autophagy and Nrf2 in regulating the American ginseng-mediated suppression of oxidative stress and inflammatory cytokine production in macrophages as well as oxidative stress, hypertrophic growth and cell death in cardiomyocytes; Aim 2. To determine the active components of American ginseng for the coordination of autophagy and Nrf2 pathway thereby blocking the vicious cycle of oxidative stress and inflammation in vitro; Aim 3. To determine the active components of American ginseng for the suppression of maladaptive cardiac hypertrophy and dysfunction via activating both myocardial autophagy and Nrf2 in the heart; These experiments will demonstrate for the first time that American ginseng-activated autophagy is essential for American ginseng-activated Nrf2-mediated cardiac protection. Overall, the outcome of this proposal will not only provide a novel molecular mechanism of American ginseng-mediated cardiac protection, but also establish biomarkers for the sub-fractionating of the active components of ginsengs for cardiac protection.